We previously reported that growth in salicylate increases the resistance of a number of Gram-negative bacteria to a variety of clinically important antibiotics. We have traced part of this effect in Escherichia coli to a cascade of molecular events initiated by induction of transcription of the marRAB (multiple antibiotic resistance) operon. One consequence of mar induction is increased transcription of micF whose mRNA is partly anti-sense to the mRNA of ompF. This results in a severe reduction in the translation of ompF mRNA into OmpF, a major outer membrane porin. The absence of OmpF reduces the permeation of the outer membrane by antibiotics. Thus, treatment with salicylate induces the same profile of antibiotic resistance that is found in rare constitutive mar mutants. In addition to the effects on micF and ompF, induction of mar increases the expression of at least 5 other genes including Mn- superoxide dismutase and glucose-6-phosphate dehydrogenase. We have now identified inaA, a weak acid inducible gene, as being regulated by mar. mar constitutive (antibiotic resistant) mutants express inaA constitutively. Furthermore, marA/B is necessary for the inducibility of inaA, but not its basal level expression. Basal level expression of inaA requires the presence of other sequences mapped to within 39 kb of mar. Substances that induce mar and inaA include weak acids (benzoate, acetylsalicylate, acetaminophen); uncouplers (2,4-dinitrophenol), antibiotics (chloramphenicol, tetracycline); and superoxide generators (paraquot, menadione). The nature of the sensor(s) involved in monitoring these seemingly diverse effectors is not known. Compounds that interfere with the sensors could reduce bacterial defense against antibiotics.